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TNF- and Calcium Signaling in Airway Smooth Muscle Cells: A Never-Ending Story with Promising Therapeutic Relevance

University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

To the Editor:

I read with great interest the article by Dr. White and colleagues in this issue of the American Journal of Respiratory Cell and Molecular Biology, describing the role of transient receptor potential channel 3 (TRPC3) in the abnormal store-operated influx of calcium induced by TNF- in airway smooth muscle (1). Although these data were generated using cultured bronchial smooth muscle cells, the observations made in this study could have important clinical consequences. The main reason why we should be inspired by these in vitro studies can be found in the recent demonstration that TNF- blockade, given either preventively in animal models of allergic asthma (2, 3) or therapeutically in patients with severe asthma (4, 5), represents a promising strategy to improve asthma symptoms, including airway hyperresponsiveness. Therefore, the essential question that should be raised is to understand how TNF-, mechanistically speaking, could participate in the pathogenesis of asthma, and more specifically in the development of airway hyperresponsiveness. One potential answer was given in the early 1990s when different studies convincingly showed that TNF- could exert deleterious effects directly on airway smooth muscle, the main effector tissue regulating the bronchomotor tone. Under the leadership of Dr. Christian Bronner, my Ph.D. supervisor, and later confirmed in collaboration with Dr. Panettieri's group, we were among the first to show the ability of TNF-, in a nonspecific (all agonists) and receptor (TNFR1)-dependent manner, to enhance calcium responses induced by G protein–coupled receptor (GPCR) agonists not only in guinea pig (6) but also in human cultured airway smooth muscle cells (7). We subsequently proposed that TNF-–airway smooth muscle interactions could play, via alterations in calcium signaling, an important role in the development of airway hyperresponsiveness seen in symptomatic individuals with asthma (8). In the same year, Renzetti and colleagues described the first pharmacologic evidence for a role of TNF- in allergen-associated airway inflammation and airway hyperresponsiveness in sensitized guinea pigs and Brown Norway rats (9). It is somewhat regrettable that this elegant study published 10 years ago was not referenced and discussed in the latest reports in humans with asthma describing the therapeutic benefit of TNF- blockade using etanercept (4, 5). Nonetheless, these studies strongly reinforce the concept that TNF- is undeniably an important player in the modulation of airflow obstruction in asthma. Whether this occurs directly on airway smooth muscle or indirectly via the action of released inflammatory mediators remains to be further investigated. In agreement with our main hypothesis, the study by Dr. White and colleagues is supportive of a direct effect on airway smooth muscle contractility. While much attention has been given to better understanding TNF-–associated mechanisms leading to enhanced GPCR agonist-evoked calcium responses (7), little information is available on the effects of inflammatory cytokines on store-operated calcium entry in human airway smooth muscle. As described in this study, we also found that TNF- could in fact enhance the sustained calcium levels during agonist-induced calcium responses, an effect that could be attributed to the increased influx of extracellular calcium through the capacitative entry model proposed by Putney. This study by Dr. White and colleagues used siRNA strategies to provide the first evidence of a potential role of TRPC3 channels in the enhanced calcium influx induced by TNF- in human airway smooth muscle. More interesting is the partial role of TRPC3 in the augmented calcium transients to acetylcholine induced by TNF-. This suggests that, in TNF-–treated cells, TRP channel could also participate in the abnormal calcium signals via the mobilization of calcium from both intracellular and extracellular spaces. TRPC3 could therefore represent one of the missing links between TNF- and the exaggerated calcium responses to GPCR agonists. Interestingly, TRPC3 has the capacity to physically interact with a multitude of key calcium regulatory proteins associated with GPCR signaling, including receptors for Inositol tris-phosphate and ryanodine, and PLC among others (10). It would be valuable to determine which TRPC3-interacting proteins mediate TNF- action. Whether TRPC3 pathways also functionally interact with other signaling proteins such as CD38 as well Rho-kinase recently involved in TNF-–enhancing effects on agonist-induced calcium responses (7) represents another interesting area of investigation. The study by Dr. White and colleagues adds another level to the complex signaling network in airway smooth muscle used by TNF- to participate in the development of airway hyperresponsiveness. TRPC3 seems to be only a part of the interminable puzzle of TNF- pathways since its inhibition partially prevented TNF-–enhancing effects on calcium signaling suggesting the involvement of other TRPC-independent pathways. The study by Dr. White and colleagues supports the notion that targeting TNF- signaling pathways including TRPC3 expression and/or function in airway smooth muscle is likely to have a therapeutic value for the treatment of airway hyper-responsiveness in asthma.

Footnotes

Conflict of Interest Statement: The author does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

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